Chronic inflammation is a potential risk factor for tumor progression. The molecular mechanisms linking chronic inflammation and tumor growth have proven elusive. Herein, we describe a new role for Toll-like receptor 4 (TLR4) in tumor-associated macrophages (TAMs) in promoting tumor growth. TAMs can remodel tumor microenvironment and promote tumor growth. With the use of mice lacking TLR4 signaling, we show that TLR4 signaling influences tumor growth and that TLR4 signaling is a critical upstream activator of nuclear factor-kappa B (NF-kappaB) in TAMs. TLR4-deficient TAMs produce neither proinflammatory cytokines nor angiogenic factors, and activate no NF-kappaB activity in tumor cells. Furthermore, using macrophage/tumor cell coculture system and adoptive transfer of macrophages with functional TLR4 macrophages to TLR4-deficient mice bearing tumors, we demonstrate an essential role for TLR4 signaling in inducing NF-kappaB activity in tumor cells and enhancing tumor growth. Antibody neutralization experiments reveal that TAMs are stimulated by heat shock proteins derived from tumor cells through TLR4, leading to production of growth factors, which may in turn promote tumor growth via NF-kappaB signal pathway. Therefore, this signaling cascade may represent a therapeutic target in cancer.